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Huang, Wenyong; He, Wenjing; Shi, Xiaomin; Ye, Qianyu; He, Xiaoshun; Dou, Lang; Gao, Yifang
doi: 10.1111/jvh.13341pmid: 32510704
Chronic hepatitis B virus (CHBV) infection is a major cause of liver diseases. Mucosal‐associated invariant T (MAIT) cells are important for antiviral immunity in the liver, but the distinction between intrasinusoidal and peripheral MAIT cells in patients with CHBV infections remains unclear. PBMCs were obtained from patients with CHBV infections (n = 29) and age‐matched controls (n = 46). Liver‐associated mononuclear cells (LMCs) were collected from healthy donors (n = 29) and explanted livers (n = 19) from patients and used for phenotypic, functional and TCR diversity analyses. The percentages of both peripheral and intrasinusoidal MAIT cells were significantly reduced in the CHBV infection group compared to the control group. Peripheral MAIT cells from CHBV‐infected patients expressed higher levels of HLA‐DR, CD69, CD38 and PD‐1 than those of controls. We also confirmed that peripheral MAIT cells in HBV patients had elevated expression T‐cell exhaustion genes. Except for a difference in the level of PD‐1, no differences were observed between the liver MAIT cells of the two groups. The production of IFN‐α in peripheral MAIT cells of CHBV infection patients was lower than in control patients, but no such difference was observed in liver MAIT cells. Additionally, a distinct TCR signature was found in CHBV patients. Hence, we found distinct activities and functions in liver and peripheral MAIT cells of patients with CHBV infections.
Othman, Bayan; Al‐Najjar, Mohammad A. A.; Othman, Dalia; Al‐Qudah, Rajaa; Basheti, Iman
doi: 10.1111/jvh.13342pmid: 32506771
This observational study was designed to assess the prevalence, knowledge and attitude of pregnant females towards hepatitis B infection, in addition to their perspective of the healthcare practice about HBV in Jordan. A randomly selected group of pregnant females visiting public gynaecology clinics in Jordan were approached to participate in the study. Blood samples were collected from the participants, and HBV markers were detected in their serum using specialized ELISA Kits to assess for the prevalence of infection. Knowledge and attitude of participants was assessed via a developed and validated questionnaire. Statistical analysis was conducted using the Statistical Package for the Social Sciences (SPSS) version 24. Blood samples (n = 300) from 330 pregnant females were collected. The prevalence of hepatitis B surface antigen (HBsAg) among the pregnant females was found to be 5%. Anti‐HBs and anti‐HBc were found to be 33.3% and 7%, respectively. No significant correlation between age, socio‐economic status and educational level was found with HBsAg positivity. Limited knowledge regarding HBV was revealed among the pregnant females (9.1%‐41.3%, P < .05). The majority had a positive attitude regarding HBV vaccination and antiviral medications in case of infectivity. More than 90% agreed on the present lack of counselling and screening of HBV they obtained during their first perinatal visit to the gynaecology clinics. This study revealed a lack of knowledge on HBV, and low counselling and screening received were reported. Policymakers need to introduce new interventions to improve the current awareness of patients and gynaecologists regarding hepatitis B infection.
Chon, Young Eun; Jung, Kyu Sik; Ha, Yeonjung; Kim, Mi Na; Lee, Joo Ho; Hwang, Seong Gyu; Ahn, Sang Hoon; Kim, Do Young; Han, Kwang‐Hyub; Park, Jun Yong
doi: 10.1111/jvh.13345pmid: 32558181
Verbinnen, Thierry; Hodari, Moana; Talloen, Willem; Berke, Jan Martin; Blue, David; Yogaratnam, Jeysen; Vandenbossche, Joris; Shukla, Umesh; De Meyer, Sandra; Lenz, Oliver
doi: 10.1111/jvh.13351pmid: 32579776
Zhang, Hongbin; Yan, Xiong; Yang, Cheng; Zhan, Qian; Fu, Yueqiang; Luo, Huating; Luo, Hongchun
doi: 10.1111/jvh.13352pmid: 32559002
Immunopathological injury induced by persistent hepatitis B virus (HBV) infection contributes to the progression from chronic hepatitis B (CHB) to hepatic cirrhosis and hepatocellular carcinoma (HCC). Regulatory T cells (Tregs), CD4+ T helper (Th) cells, and hepatic stellate cells (HSCs) are considered to be the pivotal factors during this progression. In this study, our aim was to investigate the molecular mechanisms of liver immunopathological injury associated with Tregs, CD4+ Th cells, and HSCs. Liver tissues were collected to assay the cytokines and distribution and frequencies of CD4+ Th cells and Tregs. The chemotaxis of Th17 cells towards the liver and the interactions between IL‐22, IL‐17A, and HSCs were explored. The data showed the frequencies of Th17 cells, and their effector molecules IL‐22 and IL‐17A were increased along with the severity of chronic liver diseases. However, the frequencies of Tregs were decreased in HBV‐associated cirrhotic tissues compared with those in CHB tissues and HCC tissues. hepatitis B virus X antigen (HBxAg)‐activated HSCs recruited more Th17 cells into the liver and conduced to the secretion of IL‐17A and IL‐22 that could in turn stimulate the proliferation and fibrotic marker secretion of the HSCs. Therefore, we suggest that the interactions between Th17 cells, IL‐17A, IL‐22, and HSCs form a positive feedback loop that aggravated the progression of chronic liver disease with HBV infection through the phosphoinositide‐3‐kinase/protein kinase B (PI3K/AKT) signalling pathway. Our findings indicated the IL‐17A/IL‐22 pathway might become a new treatment target for liver cirrhosis and HCC.
Deng, Yang; Li, Peng; Liu, Wenbin; Pu, Rui; Yang, Fan; Song, Jiahui; Yin, Jianhua; Han, Xue; Li, Chengzhong; Zhao, Jun; Wang, Hongyang; Cao, Guangwen
doi: 10.1111/jvh.13353pmid:
Ringlander, Johan; Skoglund, Catarina; Prakash, Kasthuri; Andersson, Maria E.; Larsson, Simon B.; Tang, Ka‐Wei; Rydell, Gustaf E.; Abrahamsson, Sanna; Castedal, Maria; Norder, Heléne; Hellstrand, Kristoffer; Lindh, Magnus
doi: 10.1111/jvh.13356pmid: 32592629
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). Integration of HBV DNA into the human genome may contribute to oncogenesis and to the production of the hepatitis B surface antigen (HBsAg). Whether integrations contribute to HBsAg levels in the blood is poorly known. Here, we characterize the HBV RNA profile of HBV integrations in liver tissue in patients with chronic HBV infection, with or without concurrent hepatitis D infection, by transcriptome deep sequencing. Transcriptomes were determined in liver tissue by deep sequencing providing 200 million reads per sample. Integration points were identified using a bioinformatic pipeline. Explanted liver tissue from five patients with end‐stage liver disease caused by HBV or HBV/HDV was studied along with publicly available transcriptomes from 21 patients. Almost all HBV RNA profiles were devoid of reads in the core and the 3′ redundancy (nt 1830‐1927) regions, and contained a large number of chimeric viral/human reads. Hence, HBV transcripts from integrated HBV DNA rather than from covalently closed circular HBV DNA (cccDNA) predominated in late‐stage HBV infection, in particular in cases with hepatitis D virus co‐infection. The findings support the suggestion that integrated HBV DNA can be a significant source of HBsAg in humans.
Choi, Hwa‐Young; Mai, Thi Ha; Kim, Kyung‐Ah; Cho, Hyunsoon; Ki, Moran
doi: 10.1111/jvh.13346pmid: 32558154
The association between hepatitis virus infection and Parkinson's disease remains controversial. To determine whether hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are associated with an increased risk of Parkinson's disease in Korean aged ≥40 years, we completed a population‐based prospective study including patients without infections and those with HBV, HCV and HBV/HCV infections from 2005 to 2015. We used the International Classification of Diseases 10th Revision to identify Parkinson's disease (G20) and chronic hepatitis C virus (B18.2) and chronic hepatitis B virus infections (B18.0 or B18.1). To identify Parkinson's disease risk, competing risk analysis adjusted for age, sex, comorbidities and death was performed. Overall, 1 010 317 patients (358 052, noninfection; 488 990, hepatitis B; 144 459 hepatitis C; and 18 680 hepatitis B/C) were included. The incidence density of Parkinson's disease per 10 000 person‐years was highest in the hepatitis C group (8.0), followed by the hepatitis B/C (6.8) and hepatitis B (5.0) groups. Hypertension, ischaemic heart disease, epilepsy, stroke and depressive disorder increased the hazard of Parkinson's disease in all groups. The adjusted hazard ratios were 1.25 (95% confidence interval: 1.17‐1.35), 1.39 (95% confidence interval: 1.27‐1.52) and 1.46 (95% confidence interval: 1.14‐1.85) in the HBV, HCV, and HBV/HCV groups, respectively. Our findings suggest that adult patient of 40 years and older with HBV and HCV infections should be monitored for signs of Parkinson's disease so that early intervention and accurate treatment can be provided for minimizing the development and consequences of Parkinson's disease.
Saine, M. Elle; Szymczak, Julia E.; Moore, Tyler M.; Bamford, Laura P.; Barg, Frances K.; Schnittker, Jason; Holmes, John H.; Mitra, Nandita; Lo Re, Vincent
doi: 10.1111/jvh.13343pmid: 32500618
Stigma around hepatitis C virus (HCV) infection is an important and understudied barrier to HCV treatment and elimination. The determinants of HCV‐related stigma, including the impacts of stage of HCV treatment (ie spontaneously cleared; diagnosed, untreated; previously treated, not cured; currently being treated; and treated, cured) and coinfection with human immunodeficiency virus (HIV), remain unknown. To address these gaps, we conducted a cross‐sectional study among patients with a history of HCV infection (n = 270) at outpatient clinics in Philadelphia from July 2018 to May 2019. We evaluated stigma using the validated HCV Stigma Scale, adapted from the Berger HIV Stigma Scale. Associations among HCV‐related stigma and hypothesized demographic, behavioural, and clinical risk factors were evaluated by multivariable linear regression. Most participants (95.5%) experienced HCV‐related stigma. Mean stigma scores did not differ significantly between HCV‐monoinfected and HIV/HCV‐coinfected participants (P = .574). However, we observed significant interactions between HIV status and multiple determinants; therefore, we stratified analyses by HIV status. Among HIV/HCV‐coinfected participants, previous HCV treatment without cure, female gender, Hispanic/Latinx ethnicity and some college education were significantly associated with higher HCV‐stigma scores. An annual income of $10 000‐$40 000 was associated with significantly lower stigma scores. No significant associations were observed among HCV‐monoinfected participants. We found that most participants experienced stigma associated with HCV diagnosis. While stigma scores were similar between HCV‐monoinfected and HIV/HCV‐coinfected participants, the determinants associated with HCV stigma differed by HIV status. Understanding how experiences of stigma differ between HCV‐monoinfected and HIV/HCV‐coinfected patients may aid in the development of targeted interventions to address the HCV epidemic.
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Long‐term suppression of hepatitis B virus with tenofovir (TDF) induces fibrosis regression, and repeated liver stiffness (LS) measurement can indicate the improvement of fibrosis. We aimed to investigate predictors for LS improvement assessed by changes in patients receiving long‐term TDF therapy in chronic hepatitis B (CHB) with liver cirrhosis. CHB patients with histologically proven liver cirrhosis who received TDF as the first‐line therapy from 2012 to 2015 were recruited. LS and controlled attenuation parameter (CAP) measurements were repeated at baseline and 3 years after therapy. Liver stiffness improvement was defined as a drop of LS value ≥30% from the baseline. A total of 131 patients were enrolled (mean age 51.4% and male 64.9%). After 3 years of TDF therapy, the mean LS value significantly improved (from 14.7 to 8.6 kPa, P < .001), and 96 (73.3%) patients have achieved LS improvement. Predictors associated with improvement of LS were low body mass index (BMI), HBeAg positivity, and low CAP value at baseline. In multivariate analysis, low BMI was a single factor independently associated with LS improvement (odds ratio 0.680, 95% CI 0.560‐0.825, P < .001). Patients with BMI < 23.5, had a 1.96 times more chance of achieving LS improvement compared to those with BMI ≥ 23.5 (90.1% vs. 46.0%, P = .001). High BMI was a single significant factor hindering the fibrosis improvement in patients receiving long‐term TDF therapy in CHB with liver cirrhosis. Life style modification and BMI reduction should be encouraged to enhance fibrosis improvement.
Four weeks of once‐daily oral JNJ‐56136379 (JNJ‐6379; 25, 75, 150 or 250 mg), a class‐N capsid assembly modulator (CAM‐N), was well tolerated with potent antiviral activity in treatment‐naïve, chronic hepatitis B e antigen–positive and hepatitis B e antigen–negative patients (NCT02662712). Hepatitis B virus (HBV) genome sequence analysis, using HBV DNA next‐generation sequence technology, was performed, and impact of substitutions on efficacy was assessed. Analyses focused on HBV core protein amino acid positions associated with JNJ‐6379 and/or other CAMs in vitro resistance, and those within the CAM‐binding pocket. 31/57 patients had ≥ 1 polymorphism at any of the core amino acid positions of interest, most frequently at positions 38 (32%), 105 (23%) and 109 (14%). None of these polymorphisms are known to reduce JNJ‐6379 in vitro activity (fold change [FC] in 50% effective concentration <3.0). Two JNJ‐6379‐treated patients carried a Y118F baseline core polymorphism known to reduce JNJ‐6379 activity in vitro (FC = 6.6) and had HBV DNA declines of 2.77 (75 mg) and 2.19 log10 IU/mL (150 mg) at the end of treatment. One 75 mg JNJ‐6379‐treated patient had an emerging T109S substitution (FC = 1.8; HBV DNA decline 3.18 log10 IU/mL). A 25 mg JNJ‐6379‐treated patient had on‐treatment enrichment of Y118F variant (HBV DNA decline 2.13 log10 IU/mL). In conclusion, baseline polymorphisms and enrichment of substitutions reducing JNJ‐6379 in vitro activity were rare, with no consistent impact on virological response during a 4‐week phase 1b study. Emergence of resistance to longer treatments of JNJ‐6379 will be evaluated in phase 2 studies.
Genetic predisposition of human leucocyte antigen (HLA)‐DR has been linked to nonresponse to hepatitis B virus (HBV) vaccination. We sought to reveal their effects on chronic infection and evolution of HBV and development of hepatocellular carcinoma (HCC). Genetic polymorphisms at HLA‐DR enhancer regions were genotyped in 4588 participants using quantitative PCR. HBV mutations were determined by sequencing. A dual‐luciferase assay was applied to detect the enhancer activity. Associations between HLA‐DR polymorphisms and postoperative prognosis were investigated in another cohort of 397 HBV‐infected HCC patients. Variant alleles (rs3135395‐T, rs3135338‐C and rs477515‐T) were significantly associated with a decreased risk of HBV persistence in Chinese patients. rs3135395‐T, rs3135338‐C, rs477515‐T and rs2395178‐G also significantly decreased HCC risk. rs3135395‐T, rs477515‐T and rs2395178‐G were inversely associated with the generation of A1762T/G1764A, T1753V and C1653T, the HCC‐risk HBV mutations. Multiplicative interactions of the variant genotypes with the HCC‐risk HBV mutations were significantly associated with a decreased risk of HCC. In multivariate Cox analysis, rs477515‐T independently predicted a favourable prognosis, with a hazard ratio of 0.48 (P = .002). The activity of the HLA‐DRB1 enhancer with rs477515‐T was significantly higher than that with rs477515‐C. The activity of the HLA‐DRB1 enhancer with rs477515‐T and that with rs477515‐C was significantly up‐regulated by interferon‐γ and interleukin‐4, respectively. Interleukin‐6 significantly inhibited the HLA‐DRB1 enhancer activity, and this effect was more evident in those carrying rs477515‐T. Polymorphisms predisposing to down‐regulation of HLA‐DR facilitate the Th1‐to‐Th2 transition and promote HCC development, possibly via selecting the HCC‐risk HBV mutations. This can be transformed into specific prophylaxis of HCC.